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Striatal Reinnervation Process after Acute Methamphetamine-Induced Dopaminergic Degeneration in Mice

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Abstract

Methamphetamine (METH), an amphetamine derivate, may increase the risk of developing Parkinson’s disease (PD). Human and animal studies have shown that METH produces persistent dopaminergic neurotoxicity in the nigrostriatal pathway, despite initial partial recovery. To determine the processes leading to early compensation, we studied the detailed morphology and distribution of tyrosine hydroxylase immunoreactive fibers (TH-ir) classified by their thickness (types I–IV) before and after METH. Applying three established neurotoxic regimens of METH: single high dose (1 × 30 mg/kg), multiple lower doses (3 × 5 mg/kg) or (3 × 10 mg/kg), we show that METH primarily damages type I fibers (the thinner ones), and to a much lesser extend types II–IV fibers including sterile axons. The striatal TH terminal partial recovery process, consisting of a progressive regrowth increases in types II, III, and IV fibers, demonstrated by co-localization of GAP-43, a sprouting marker, was observed 3 days post-METH treatment. In addition, we demonstrate the presence of growth-cone-like TH-ir structures, indicative of new terminal generation as well as improvement in motor functions after 3 days. A temporal relationship was observed between decreases in TH-expression and increases in silver staining, a marker of degeneration. Striatal regeneration was associated with an increase in astroglia and decrease in microglia expression, suggesting a possible role for the neuroimmune system in regenerative processes. Identification of regenerative compensatory mechanisms in response to neurotoxic agents could point to novel mechanisms in countering the neurotoxicity and/or enhancing the regenerative processes.

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Abbreviations

A-Cu-Ag:

Amino-cupric silver

DAT:

Dopamine transporter

GAP-43:

Anti-growth associated protein-43

PB:

Phosphate buffer

PBST:

Phosphate buffer with Triton

SNpc:

Substantia nigra pars compacta

TH-ir:

Tyrosine hydroxylase immunoreactivity

MPTP:

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine

6-OHDA:

6-Hydoxydopamine

MDMA:

3,4-Methylenedioxy-methamphetamine

METH:

Methamphetamine

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Acknowledgements

This work was supported by grants from the Spanish Ministry of Sanidad, Servicios Sociales e Igualdad, PNSD 2016/033, CIBERNED CB06/05/0055, Spanish Ministry of Economía y Competitividad, grant references: SAF2016-78207-R and PCIN-2015-098, and Fundacion Ramon Areces 172275. The authors want to specially thank Dr. Juan de Carlos for his help in providing an original figure by Ramon y Cajal that was used for this article, and Mrs. Emilia Rubio and Beatriz Pro for their excellent technical assistance.

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  1. Noelia Granado and Sara Ares-Santos contributed equally to this work.

Authors and Affiliations

  1. Instituto Cajal, Consejo Superior de Investigaciones Científicas, CSIC, Avda Dr Arce 37, 28002, Madrid, Spain

    Noelia Granado, Sara Ares-Santos & Rosario Moratalla

  2. CIBERNED, ISCIII, Madrid, Spain

    Noelia Granado, Sara Ares-Santos & Rosario Moratalla

  3. Department of Pharmacology, Howard University College of Medicine, Washington DC, USA

    Yousef Tizabi

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  1. Noelia Granado
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  2. Sara Ares-Santos
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  4. Rosario Moratalla
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Correspondence to Rosario Moratalla.

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All experimental procedures conformed to European Community guidelines (2003/65/CE) and were approved by Cajal Institute’s Bioethics Committee (following DC86/609/EU).

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Granado, N., Ares-Santos, S., Tizabi, Y. et al. Striatal Reinnervation Process after Acute Methamphetamine-Induced Dopaminergic Degeneration in Mice. Neurotox Res 34, 627–639 (2018). https://doi.org/10.1007/s12640-018-9925-z

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